Genetic modulation of TLR8 response following bacterial phagocytosis

Human Toll‐like receptors (TLRs) TLR7, TLR8, and TLR9 are important immune sensors of foreign nucleic acids encountered by phagocytes. Although there is growing evidence implicating TLR7 and TLR9 in the detection of intracellular pathogenic bacteria, characterization of such a role for TLR8 is currently lacking. A recent genetic study has correlated the presence of a TLR8 single nucleotide polymorphism (SNP) (rs3764880:A>G; p.Met1Val) with the development of active tuberculosis, suggesting a role for TLR8 in the detection of phagosomal bacteria. Here we provide the first direct evidence that TLR8 sensing is activated in human monocytic cells following Helicobacter pylori phagocytosis. In addition, we show that rs3764880 fine tunes translation of the two TLR8 main isoforms, without affecting protein function. Although we show that TLR8 variant 2 (TLR8v2) is the prevalent form of TLR8 contributing to TLR8 function, we also uncover a role for the TLR8 long isoform (TLR8v1) in the positive regulation of TLR8 function in CD16⁺CD14⁺ differentiated monocytes. Thus, TLR8 sensing can be activated following bacterial phagocytosis, and rs3764880 may play a role in the modulation of TLR8‐dependent microbicidal response of infected macrophages. Hum Mutat 31:1069–1079, 2010. © 2010 Wiley‐Liss, Inc.     

Hematopoietic stem cell-derived pericytic cells in brain tumor angio-architecture

Bone marrow-derived cells are recruited into tumor vasculature in response to angiogenic signals, and some of the cells within the newly forming tumor vessels are hematopoietic stem cells (HSCs) in origin. Previous studies suggest that bone marrow-derived pericytes are associated with newly formed vessels in tumors. In this study, we used an orthotopic rat glioma model (RT-2/RAG) to examine the contribution of long-term hematopoietic stem cell (LT-HSC)-derived pericytic cells to brain tumor angiogenesis. Mice (RAG-2/KO5.2) were lethally irradiated, and their hematopoietic cells were repopulated by transplantation of double fluorescence-activated cell-sorted LT-HSCs that express green fluorescent protein (GFP+). RT-2/RAG cells were then injected into the striatum of the chimeric mice 6 weeks post-transplantation. The animals were sacrificed 9 days after tumor implantation, and the incorporation and lineage-specific marker expression profile of the GFP+ cells within the growing tumor and tumor periphery were analyzed. LT-HSC-derived GFP+ cells were noted to incorporate onto the surface of tumor vessels within the perivascular space. LT-HSC-derived GFP+ cells express the pericyte progenitor marker, platelet-derived growth factor receptor-beta (PDGFR beta), as well as mature perictyte markers such as nerve/glial antigen 2 proteoglycan (NG2), alpha-smooth muscle actin (alpha SMA), and desmin. These LT-HSC-derived cells may represent a population of progenitor or committed pericytes within the neovascular tree and may play a role in shaping the angio-architecture in the vascular niche of brain tumors.     

A central role for peripheral dendritic cells in the induction of acquired thymic tolerance

Despite extensive negative selection in the thymus, numerous clones of self-reactive T cells are normally exported to the periphery. In most instances, autoimmunity is prevented by regulatory T (Tr) cells, many of which are also of recent thymic origin. We have demonstrated recently that natural killer (NK) Tr thymocytes (THYr) can be induced by the injection of antigen into the eye, an immunologically privileged site; and that the intravenous infusion of antigen-presenting cells (APCs) from such animals also induces NKT THYr. Furthermore, we have also observed that some of these APCs migrate to the thymus as CD11c(+) dendritic cells (DCs). Other authors have correlated the migration of DCs to the thymus with the generation of CD4(+)CD25(+) THYr. We therefore propose a novel tolerance induction pathway by which tolerogenic DCs routinely transport antigen (both self and nonself) from the periphery to the thymus, where they positively select THYr. We also propose that the ability of tolerogenic DCs to induce acquired thymic tolerance on demand might have important implications for the immunotherapy of autoimmunity and allotransplantation.     

Attitudes to specialist palliative care and advance care planning in people with COPD: a multi-national survey of palliative and respiratory medicine specialists

Background

Chronic obstructive pulmonary disease (COPD) guidelines recommend early access to palliative care together with optimal, disease-directed therapy for people with advanced disease, however, this occurs infrequently. This study explored the approaches of respiratory and palliative medicine specialists to palliative care and advance care planning (ACP) in advanced COPD.

Methods

An online survey was emailed to all specialists and trainees in respiratory medicine in Australia and New Zealand (ANZ), and to all palliative medicine specialists and trainees in ANZ and the United Kingdom.

Results

Five hundred seventy-seven (33.1%) responses were received, with 440 (25.2%) complete questionnaires included from 177 respiratory and 263 palliative medicine doctors. Most respiratory doctors (140, 80.9%) were very or quite comfortable providing a palliative approach themselves to people with COPD. 113 (63.8%) respiratory doctors recommended referring people with advanced COPD to specialist palliative care, mainly for access to: psychosocial and spiritual care (105, 59.3%), carer support (104, 58.5%), and end-of-life care (94, 53.1%). 432 (98.2%) participants recommended initiating ACP discussions. Palliative medicine doctors were more likely to recommend discussing: what palliative care is (p <?0.0001), what death and dying might be like (p?<?0.0001) and prognosis (p =?0.004). Themes highlighted in open responses included: inadequate, fragmented models of care, with limited collaboration or support from palliative care services.

Conclusions

While both specialties recognised the significant palliative care and ACP needs of people with advanced COPD, in reality few patients access these elements of care. Formal collaboration and bi-directional support between respiratory and palliative medicine, are required to address these unmet needs.

     

Asymptomatic Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery

Anomalous origin of the left coronary artery from the pulmonary artery is a rare congenital anomaly of the coronary arteries which usually presents with heart failure in early infancy. We describe the unusual occurrence of this in an older child with no signs of cardiac ischemia. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Chondrocyte autophagy is stimulated by HIF-1 dependent AMPK activation and mTOR suppression

The goal of the study is to examine the relationship between the sensor molecules, Hypoxia Inducible Factor-1 (HIF-1), AMP activated Protein Kinase (AMPK) and mammalian Target of Rapamycin (mTOR) in chondrocyte survival and autophagy. We showed that chondrocytes expressed the energy sensor AMPK-1 and that activation increased with maturation. In addition, we showed that thapsigargin treatment activated AMPK and autophagy in a HIF-1-dependent manner. Using serum-starved AMPK-silenced cells, we demonstrated that AMPK was required for the induction of the autophagic response. We also noted a change in chondrocyte sensitivity to apoptogens, due to activation of caspase-8 and cleavage and activation of the pro-apoptotic protein, BID. To test the hypothesis that AMPK signaling directly promoted autophagy, we inhibited AMPK activity in mTOR silenced cells and showed that while mTOR suppression induced autophagy, AMPK inhibition did not block this activity. Based on these findings, it is concluded that because of the micro-environmental changes experienced by the chondrocyte, autophagy is activated by AMPK in a HIF-1-dependent manner.     

HIV-positive patients with nonalcoholic fatty liver disease have a lower body mass index and are more physically active than HIV-negative patients

OBJECTIVE: To determine whether the clinical and metabolic features associated with nonalcoholic fatty liver disease (NAFLD) are similar between HIV-positive and HIV-negative male subjects. METHODS: Twenty-six HIV-positive and 25 HIV-negative subjects with liver biopsy-proven NAFLD were compared for liver histology (extent of steatosis, steatosis grading, and fibrosis staging), blood biochemistry (glucose, insulin, C-peptide, hemoglobin A1c, and lipid profile), insulin resistance (IR) using a homeostasis model assessment, anthropometry (body mass index [BMI], waist circumference, and arm muscle area), dietary intake, and physical activity. RESULTS: The 2 groups were similar for age, liver histology, and IR. HIV-positive patients had a lower BMI (26.3 +/- 0.5 vs. 30.2 +/- 1.0 kg/m; P = 0.001) and lower percentage of fat mass (19.4 +/- 0.9 vs. 22.7 +/- 1.2; P = 0.026) when compared with HIV-negative patients. Although caloric intake was similar between groups, HIV-positive patients had a higher physical activity level (8.3 +/- 1.6 vs. 4.1 +/- 0.8 units of exercise per day; P = 0.029). Blood triglycerides were significantly higher (3.14 +/- 0.39 vs. 1.86 +/- 0.20 mmol/L; P = 0.006) in HIV-positive patients. CONCLUSION: Although NAFLD was similar between the 2 groups, HIV-positive patients had a lower BMI and were more physically active compared with HIV-negative patients. This may suggest that in HIV, NAFLD is associated with factors other than those related to body fatness, such as HIV infection and treatment.